The goal of this competitive renewal application is to define those mechanisms that account for PA's effects on mammary carcinogenesis and that are dependent on PA intensity and duration, and independent of differences in body weight. Three specific aims are proposed:1) How does PA intensity inhibit the carcinogenic process? A range of PA intensities will be investigated to test the linearity of the carcinogenic response. This will permit evaluation of the hypothesis that PA, in proportion to its intensity, inhibits mammary carcinogenesis by suppressing mTOR activation. Experiments are also proposed to determine if PA suppresses mTOR via its effect on circulating levels of insulin-like growth factor-1 (IGF-1); 2) How does increasing PA duration diminish cancer inhibitory activity? Our data clearly indicate that cancer inhibitory activity decreases with increasing PA duration. The non linear (J or U-shaped) carcinogenic response to PA duration is referred to as hormesis, a physiological cellular stress response. The objective of this aim is to identify the target signaling pathway accounting for the hormetic response and the connection between PA and that pathway. If mTOR-IGF-1 is not explanatory, alternative hypothesis centers on sirtuins and forkhead transcription factors (FOXO) by IL-6;and 3) How does PA affect the expansion of tumor mass in mammary carcinomas? After mammary tumors reach a measurable size, PA will be initiated with the objective of identifying subcategories of tumors (initially categorized by estrogen and progesterone receptor status and Her-2/Neu expression) that regress in response to PA; mechanisms that account for regression will be identified. Our hypothesis is that PA limits the amount of energy substrates reaching mammary carcinomas thereby inducing apoptosis by reversing tumor-associated metabolic reprogramming. The proposed pre-clinical experiments have the potential to facilitate the translation of pre-clinical and clinical research to public health recommendations for PA directed to cancer prevention and control. PUBLIC HEALTH RELEVANCE: Investigations into the effects of physical activity (PA) on various aspects of carcinogenesis in human populations involve an effort to quantify a very heterogeneous set of PA exposures. While such efforts are difficult and many limitations are widely recognized, there is substantial evidence supporting the existence of an inverse relationship between PA and cancer incidence and cancer-related mortality. In a recently released 2008 NIH Report on Physical Activity and Health, which reviewed the world's literature on physical activity and health, it was concluded that the evidence is strong that a reduction in risk for breast cancer is associated with moderate to vigorous PA. Estimates of the affect size ranged from 20% - 80% reduction in risk from the majority of reported cohort studies and 20% - 70% from a number of population-based case-control studies. The expert panel concluded that the risk reduction is likely to range from 20 to 40%, and that there are direct effects of PA on breast cancer that are distinct from the effects of PA associated with weight control. Many experts contend that a primary factor that accounts for the global epidemic of overweight and obesity is physical inactivity. This leads to the public health recommendation that individuals should increase their level of PA. However, the focus on PA to control weight gain, while critical, tends to distract attention from the fact that 40% of women are an appropriate weight for their height. Importantly, for those individuals who are maintaining body weight in an acceptable range for cancer risk reduction, but who also wish to exercise for further reduction in risk, the relative importance of exercise intensity, duration, and frequency for cancer prevention is unclear and requires investigation. The work proposed in this project specifically addresses this population of women. As noted in the recently released NIH report on Physical Activity and Health, key translational questions remain unanswered about the intensity and duration of PA that prevent and control cancer and the nature of the dose response is unclear. Given evidence that breast cancer mortality also appears to be decreased by PA and that physical activity is increasingly being recommended during and after cancer treatment, work also is proposed to inform understanding of how PA affects the growth of established breast tumors and to identify the molecular characteristics of the breast cancers that PA affects. The proposed pre-clinical experiments address gaps in our knowledge about PA and cancer identified in the 2008 NIH Report on Physical Activity and Health. The data obtained has the potential to facilitate the translation of pre-clinical and clinical research to public health guidelines for PA directed to cancer prevention and control.